Genome-wide analysis of N1ICD/RBPJ targets in vivo reveals direct transcriptional regulation of Wnt, SHH, and hippo pathway effectors by Notch1.

Document Type

Article

Publication Date

4-2012

Keywords

Adaptor Proteins, Signal Transducing, Animals, Cell Division, Cell Proliferation, Chromatin Immunoprecipitation, Gene Expression Regulation, Genome, Hedgehog Proteins, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Mice, Neural Stem Cells, Phenotype, Phosphoproteins, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Receptor, Notch1, Signal Transduction, Stem Cells, Transcription, Genetic, Transcriptome, Wnt Proteins

JAX Source

Stem Cells 2012 Apr; 30(4):741-52.

PMID

22232070

Volume

30

Issue

4

First Page

741

Last Page

752

ISSN

1549-4918

Abstract

The Notch pathway plays a pivotal role in regulating cell fate decisions in many stem cell systems. However, the full repertoire of Notch target genes in vivo and the mechanisms through which this pathway activity is integrated with other signaling pathways are largely unknown. Here, we report a transgenic mouse in which the activation of the Notch pathway massively expands the neural stem cell (NSC) pool in a cell context-dependent manner. Using this in vivo system, we identify direct targets of RBPJ/N1ICD in cortical NSCs at a genome-wide level through combined ChIP-Seq and transcriptome analyses. Through a highly conservative analysis of these datasets, we identified 98 genes that are directly regulated by N1ICD/RPBJ in vivo. These include many transcription factors that are known to be critical for NSC self-renewal (Sox2, Pax6, Tlx, and Id4) and the transcriptional effectors of the Wnt, SHH, and Hippo pathways, TCF4, Gli2, Gli3, Yap1, and Tead2. Since little is known about the function of the Hippo-Yap pathway in NSCs, we analyzed Yap1 expression and function in NSCs. We show that Yap1 expression is restricted to the stem cell compartment in the developing forebrain and that its expression is sufficient to rescue Notch pathway inhibition in NSC self-renewal assays. Together, results of this study reveal a previously underappreciated complexity and breadth of Notch1 targets in vivo and show direct interaction between Notch and Hippo-Yap pathways in NSCs.

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